Azotemia Workup

For the initial evaluation, obtain a complete blood count (CBC), a biochemical profile, urinalysis, and urine electrolyte concentrations. In addition to establishing the presence of systemic disease, these tests may reveal clues to the origin of the azotemia. Diagnostic indices are commonly used to differentiate prerenal azotemia from intrarenal or postrenal azotemia (see in the image below).

Diagnostic indices in azotemia. Although such indices are helpful, it is not necessary to perform all these tests on every patient. Comparison should always be made with patients' baseline values to identify trends consistent with increase or decrease in effective circulating volume. Use of some of these indices may be limited in certain clinical conditions, such as anemia (hematocrit), hypocalcemia (serum calcium), decreased muscle mass (serum creatinine), liver disease (blood urea nitrogen [BUN], total protein, and albumin), poor nutritional state (BUN, total protein, and albumin), and use of diuretics (urine sodium). Fractional excretion of urea and fractional excretion of trace lithium appear to be superior for assessing prerenal status in patients on diuretics.

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Prerenal azotemia

In prerenal azotemia, hemoconcentration results in elevation of the hematocrit and total protein/albumin, calcium, bicarbonate, and uric acid levels from baseline values. Urinary findings include the following:

• Oliguria (urine volume <  500 mL/day) or anuria (<  100 mL/day)
• High specific gravity (> 1.015)
• Normal sediment
• Low sodium (<  20 mEq/L; fractional excretion of sodium [FENa] <  1%)

When volume depletion is predominant, exaggerated proximal tubular reabsorption results in azotemia, hypernatremia, and elevated levels of calcium, uric acid, and bicarbonate, whereas hemoconcentration results in elevation of total protein, albumin, and hematocrit levels from baselines. Patients with hypoperfusion due to decreased cardiac output or effective arterial volume is present, patients exhibit edema, hyponatremia, and hypoalbuminemia. Hematocrit and calcium, uric acid, and bicarbonate levels vary widely. These patients often are critically ill.

The FENa has traditionally been used to differentiate prerenal azotemia from ATN. An FENa below 1% suggests a prerenal cause (eg, volume depletion), whereas an FENa above 2% suggests acute tubular necrosis (ATN). Because the FENa is based on the fact that sodium reabsorption is enhanced in the setting of volume depletion, active use of diuretics may elevate the FENa even when volume depletion is present, yielding misleading values.

Alternatives to the FENa in this setting include the fractional excretion of urea or urea nitrogen (FEUrea) and the fractional excretion of uric acid (FEUA); excretion of urea and uric acid excretion is not influenced by diuretics. An FEUrea below 35% or an FEUA below 9-10 % suggests a prerenal etiology of acute kidney injury (AKI), whereas an FEUrea above 50% or an FEUA above 10-12 % suggests acute tubular necrosis (ATN). ^[10]

Intrarenal azotemia

On blood studies, findings that may suggest intrarenal azotemia include the following:

• Anemia
• Thrombocytopenia
• Hypocalcemia
• High–anion gap metabolic acidosis
• Plasma BUN–creatinine ratio <  20

On urine studies, findings that may suggest intrarenal azotemia include the following:

• Low specific gravity (< 1.015)
• Active sediment (see Pathophysiology)
• High sodium (> 40 mEq/L; FENa > 5%)
• Low osmolality

In patients with long-standing chronic kidney disease (CKD), renal ultrasonography usually shows small, contracted kidneys. However, normal-sized or large kidneys may be seen in CKD from some causes, such as HIV nephropathy, diabetes, and renal amyloidosis. The renal sonogram usually is diagnostic for patients with polycystic kidney disease. In patients with active urinary sediment, progressive azotemia, proteinuria, or normal-sized kidneys on ultrasonography, a kidney biopsy should be considered. Consultation with a nephrologist is imperative in all such patients.

Postrenal azotemia

Urinary indices in postrenal azotemia due to complete bilateral obstruction are usually nondiagnostic. The prima facie finding here is anuria, occasionally accompanied by hypertension. Urine output still may be present if overflow (in bladder outlet obstruction) or partial ureteral obstruction is present.

A Foley catheter should be inserted as part of the initial evaluation to rule out obstruction below the bladder outlet. Unilateral ureteral obstruction rarely leads to azotemia; it occurs acutely (as a result of obstruction from calculi, papillary necrosis, or hematoma), producing renal colic, or may be chronic and asymptomatic, producing hydronephrosis.

Bilateral partial obstruction may be associated with azotemia in the presence of normal urine output. When patients are subjected to maneuvers that increase urinary flow (eg, diuretic renography or perfusion pressure flow studies), they may exhibit an increase in size or pressure of the collecting system or experience pain.

In addition to azotemia, polyuria due to loss of concentrating ability and type 1 renal tubular acidosis, with hyperkalemia, hypercalcemia from a metastatic pelvic tumor, and elevated prostate-specific antigen (PSA) levels, may be clues to postrenal azotemia. Hydronephrosis in the absence of hydroureter may be seen in early (<  3 days) obstruction, retroperitoneal process, or partial obstruction.

Renal ultrasonography (see below) is the test of choice for ruling out obstructive uropathy. If the renal sonogram is equivocal, a furosemide (Lasix) washout scan (see Radionuclide Studies) should be performed.

Renal ultrasonography is the most commonly used renal imaging study because of its ease of use and broad applicability for the following purposes ^[11] :

• Determination of kidney size and echogenicity, which is important when considering kidney biopsy; small echogenic kidneys (<  9 cm) may suggest scarring from advanced renal disease, whereas normal or large kidneys with smooth contours may indicate a potentially reversible process

• Differentiation of cystic lesions from solid lesions

• Diagnosis of urinary tract obstruction (for which it is the test of choice)

• Detection of kidney stones

Doppler renal ultrasonography can be used to evaluate renal vascular flow (eg, for identification of renal vein thrombosis, renal infarction, or renal artery stenosis).

Computed tomography (CT) ^[12] is complementary to ultrasonography, especially when the diagnosis is uncertain. Contrast nephrotoxicity should be weighed against the benefits. CT is used for the following purposes:

• Differentiation of neoplastic lesions from simple cysts (in most cases)
• Radiologic diagnosis of renal stone disease, including radiolucent stones
• Evaluation and staging of renal cell carcinoma
• Diagnosis of renal vein thrombosis
• Diagnosis of polycystic kidney disease; it is more sensitive than ultrasonography for this task, particularly in younger patients

Knipp et al describe successful use of a technique for computed tomographic angiography (CTA) of the abdomen and pelvis in azotemic patients that uses a reduced iodinated contrast volume and low kilovolt (peak) [80-kV(p)] with iterative reconstruction. Their retrospective study in 103 patients with end-stage renal disease found that this technique allows for satisfactory abdominal/pelvic CTA with a 50% reduction in contrast volume and a 43% mean radiation dose reduction, compared with a standard 120-kV(p) CTA protocol. ^[13]

Magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) is used only when CT and ultrasonography are nondiagnostic. These modalities are standard for diagnosis of renal vein thrombosis and are also used in the evaluation of renal cell carcinoma and renal artery stenosis or vasculitis.

If symptoms suggest nephrolithiasis, a plain film of the abdomen is performed to screen for presence of a radiopaque stone. Calcium-containing, struvite, and cystine stones can be identified, but radiolucent ones, such as uric acid stones, will be missed.

Intravenous pyelography (IVP) can provide detailed information concerning calyceal anatomy and the size and shape of the kidney. It is extremely useful for detecting renal stones. IVP is the preferred technique for evaluation and diagnosis of certain structural disorders (eg, chronic pyelonephritis, medullary sponge kidney, and papillary necrosis). It can provide data on the degree of obstruction. The risk of contrast nephrotoxicity should be weighed against the benefits of making a diagnosis that will not change management.

Retrograde or anterograde pyelography is of limited usefulness now that renal ultrasonography is more widely available. It may be used in patients with a high index of suspicion for hydronephrosis in whom sonograms appear normal, such as those with retroperitoneal fibrosis.

Renal arteriography is used in polyarteritis nodosa and renal artery stenosis to demonstrate multiple aneurysms or stenoses. Because of the availability of procedures that do not require contrast material (eg, ultrasonography, MRI, and MRA) and thus do not carry a risk of contrast nephrotoxicity, this test is less commonly used than it once was.

Renal venography is the standard for diagnosis of renal vein thrombosis. However, it poses a risk of contrast nephrotoxicity.

Technetium-99m dimercaptosuccinic acid (^99mTc DMSA) is heavily distributed within the renal parenchyma at first pass and so is best for detecting renal parenchymal scarring.

Technetium diethylenetriamine pentaacetic acid (^99mTc DTPA) is heavily filtered at first pass and therefore is best for qualitative assessment of kidney function (filtration and excretion). Because it is heavily filtered, it is most sensitive in detecting urine leaks after kidney transplantation. For the same reason, it is also used concomitantly with a furosemide washout scan (see below) for assessing functional obstruction of the collecting system.

Mercaptoacetyltriglycine (MAG3) is evenly distributed at first pass in the kidney and so is best for qualitative assessment of perfusion, filtration, and excretion. It is the preferred test for assessing those 3 aspects of function after kidney transplantation. It can be used with furosemide to detect urine leaks or functional obstruction, though ^99mTc DTPA scanning remains the test of choice for these conditions. Voiding cystourethrography can be performed with a radionuclide study to detect vesicoureteral reflux.

In a furosemide washout scan, the renal scan usually is performed first. Then, if needed, the furosemide washout is done after the radionuclide has accumulated in the collecting system. Furosemide is used as a part of the renogram to separate nonobstructive hydronephrosis from obstructive hydronephrosis. If there is no obstruction, furosemide-induced flow containing little or no radionuclide will fill the collecting system, washing out radionuclide-containing urine. If obstruction is present, the radionuclide is not washed out as quickly.

The half-life or clearance of the radioisotope is plotted on a curve. A half-life shorter than 10 minutes is considered normal, one longer than 20 minutes is considered obstruction, and one of 10 to 20 minutes is subject to further interpretation.

Conditions that can make it difficult to interpret the furosemide washout curve include a megaureter or pelvis that accepts a large bolus of urine and poor kidney function. In patients with a megaureter, it can be difficult to determine when the renal pelvis is full, and in patients with kidney disease, the onset of furosemide action may be delayed. To overcome the problem of poor kidney function or relative hypovolemia if a patient has been fasting, the patient should be well hydrated with intravenous (IV) fluids before the study.

The test also is operator dependent, in that the furosemide should be administered at a time when the renal pelvis is believed to be full. A full bladder also delays washout of isotope. Therefore, the patient’s bladder must be catheterized before the study can be performed.

When glomerulonephritis, vasculitis, and (occasionally) interstitial nephritis are suspected, kidney biopsy is indicated to establish the correct diagnosis and guide therapy. The following are common indications for kidney biopsy:

• Isolated glomerular proteinuria or hematuria
• Nephrotic syndrome
• Acute nephritic syndrome
• Unexplained acute or subacute kidney injury

Percutaneous kidney biopsy is associated with potential complications. Severe bleeding causing hypotension occurs in 1-2% of patients. Bleeding necessitating transfusion occurs in about 0.1-0.3% of patients. Bleeding complications can be minimized by performing pre-procedure coagulation studies: bleeding time, prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count.

Nonsteroidal anti-inflammatory drugs (NSAIDs) should be stopped at least 1 week before a scheduled elective biopsy. Patients on warfarin should be started on heparin at least 3 days before kidney biopsy. Patients who are taking heparin for other reasons should stop the drug for at least 1 day.

Contraindications for percutaneous kidney biopsy include the following:

• Uncorrectable bleeding diathesis
• Small kidneys
• Severe hypertension
• Multiple bilateral cysts or renal tumor
• Hydronephrosis
• Active renal or perirenal infection
• Uncooperative patient

Percutaneous biopsy may be performed in selected patients with a solitary kidney because of the generally low risk of bleeding. Open biopsy may be performed if a percutaneous attempt is either unsuccessful or contraindicated and if the benefits of diagnosis outweigh the risks. When percutaneous biopsy is contraindicated but a diagnosis is necessary, a transvenous transjugular renal core biopsy can be performed. ^[14] With this approach, bleeding occurs intravascularly, thereby reducing the risk of hematoma.